Dimeric steroid-21-alkyl-carbonates and process for their manufacture

ABSTRACT

BIS7STEROID-21)-ALKYL CARBONATES HAVING ANTI-INFLAMMATORY ACTIVITY ARE PREPARED BY REACTING CORTICOSTEROIDS WITH BIS-CHLOROFORMIATES.

United States Patent US. Cl. 260--397.45 Claims ABSTRACT OF THEDISCLOSURE Bis[steroid 21] alkyl carbonates having anti-infiammatoryactivity are prepared by reacting corticosteroids withbis-chloroformiates.

The present invention relates to new bis-[steroid-21]- alkyl-carbonatesof the general formula i z z I in which X represents 1 or 2 hydrogenatoms or the groupings OH H or F H 011, =0 H, 11;

Y represents a hydrogen atom or a fluorine atom; Z represents a hydrogenor fluorine atom or a methyl group; R represents an open-chain or cyclicalkylene radical which may be branched and/or interrupted by oxygenatoms, or an aralkylene or arylene radical; R represents a hydrogen atomor the hydroxy group; and R represents a hydrogen atom, a methyl groupin aor ,8- position, a

fluorine atom or a methylene group 'which may be substituted by one ortwo fluorine atoms; and double bonds or oxido groups may also be presentin 1,2-, 6,7- or 9,11- position.

The present invention, furthermore, relates to a process for themanufacture of compounds of the general Formula I, which comprisesreacting corticosteroids of the general Formula II onion :0 X CH l E /VR3 E Z n in which X, Y, Z, R and R are defined as above, and

3,663,579 Patented May 16, 1972 "Ice X may also represent a keto group,with a bis-chlorofornnate of the general Formula III 0 C1 C -OR10(Cl IIIin which R is defined as above, and if desired, subsequently introducingone or several fluorine atoms or a double bond in 1,2- and/ or6,7-position and/ or reducing a ll-keto-group.

The corticosteroids used as starting substances are generally known. Assuch there may be mentioned:

cortisone,

hydrocortisone,

Reichsteins substance S.

prednisone,

predisolone,

6u-methylprednisolone,

16uor lfifi-methylprednisolone,

9a-fluoroor 9u-chloro-prednisolone,

l6-methylene-prednisolone,

6u-methyl-9a-fluoro-prednisolone,

6a-fluoro-prednisolone,

9a-fiuoro-l6a-methyl-prednisolone,

9a-fluoro-prednisolone,

9a-fluoro-1d-methyl-prednisolone,

6a-fluoro-16u-methyl-prednisolone,

Got-fluoro-l6/3-methyl-prednisolone,

6a-fluoro-l6-methylene-prednisolone,

6a,9a-difluoro-16u-methyl-prednisolone,

6a,9a-difluoro-l6B-methyl-prednisolone,

6u,9a-difluorol G-methylene-prednisolone,

17a,2l-dihydroxy-A -pregnadiene-dione-(3,20)

17a,2l-dihydroxy-9;3,11fi-oxido-A -pregnene-dione- 17a,21-dihydroxy-9u,1 lfl-dichloro-A -pregnadiene dime-(3,20)

17a,2l-dihydroxy-A -pregnadiene-dione-(3,20

desoxycorticosterone,

corticosterone,

16zx-methyl-corticosterone,

9a-fluoro-l6a-methyl-corticosterone,

As bisfunctional alkylor aralkylor arylcholroformic acid esters(-chloroformiates), there may be mentioned, for example:Alkyl-bischloroformiates of the formula in which n is an integer of from2 to 18.

Di-, tri-, tetra-, penta-, hexa-, hepta-, or octaethylene glycolbis-chloroformiate, neopentyl-glycol bis-chloroformiate or cyclicalkylene-bis-chloroformiates such as cisortrans-cyclohexylene-[1,4-bis-chloroformiate], 1,4-dimethyl-cyclohexylene-[1,4-bis-chloroformiate], 2,2,4,4-tetramethyl-cyclobutylene [1,3 bis chloroformiate],phenylene-[1,4-bis-chloroformiate] or 1,4-dimethylphenyl-[-bis-chloroformiate] may also be used.

The bisfunctional alkyl-bis-chloroformiates are prepared by knownmethods, for example according to Nippon Kagaku Zasski, 82,606 (1961);US. Pats. No. 2,629,731 and No. 3,096,359; I. Am. Chem. Soc. 74, 3215(1952), 77, 3145 (1955) or Belgian Pat. No. 593,044.

The process of the invention is carried out by dissolving 2mol-equivalents of the steroid component in a neutral inert solvent, forexample ethers such as dioxane, tetrahydrofurane, or diglym;hydrocarbons such as benzene, toluene, or cyclohexane, methylenechloride; chloroform; or in a mixture of the above solvents. In order toeliminate hydrohalic acid that has formed, an additional amount of from1 to 1,000 mol-equivalents of a tertiary base, such as pyridine,quinoline, triethylamine, or dimethylaniline, is added. It is, however,also possible to use inorganic bases, for example sodium bicarbonate orcalcium carbonate, to eliminate the acid. Subsequently 1 or 2mol-equivalents, preferably 1 mol-equivalent, of one of theabove-specified alkyl-bis-chloroformiates is added dropwise, if desiredin one of the above-specified solvents, at temperatures of from 40 C. tothe boiling points of the solvents used, preferably from C. to 25 C. Thereaction mixture is then left to stand for 1 to 120 hours attemperatures of from 40 C. to the boiling point of the solvent,preferably from 0 C. to 25 C. The reaction mixture is then poured ontowater to which sodium bicarbonate may be added, whereupon the reactionproducts, generally, precipitate in crystalline form, in many cases onlyafter a considerable time. Reaction products which remain oily areobtained in a pure (oily or crystalline) form by shaking them withsuitable extracting agents. The reaction products may be purified, ifrequired, by recrystallization or by chromatography; in many cases, itis sufiicient to digest them thouroughly in a solvent in which thereaction product concerned is not soluble, or is as sparingly soluble aspossible, for example diethyl ether or cyclohexane or a mixture of both.

After the compounds II have been reacted with the bischloroformiatesIII, it is, of course, also possible to introduce one or more fluorineatoms, for example via the corresponding oxido compounds in the 6,9-and/or 16- position, if in the compounds of Formula II at least one ofthe radicals Y, Z or R does not represent a fluorine atom. Double bondsmay also, subsequently, be introduced in the usual manner, for exampleby oxidation with selenium dioxide or chloranil. Even a ll-oxo groupmay, subsequently, be reduced in the usual manner to yield a ll-hydroxygroup.

The products of the invention have valuable pharmacological properties.In particular they have an antiinflammatory activity and are superior toknown compounds, for example to 2l-desoxy-6-methyl-9-fluoroprednisolone.The bis [corticosteroid-21] alkyl-carbonates, surprisingly, show aconsiderably higher antiinflammatory activity than the monomeric21-carbonates.

For example, the dimeric corticosteroid product diethylene glycolbis-[6a,9m-difluoro-l6a-methyl-prednisolone]-21-carbonate (I) preparedaccording to Example 6 of the invention was compared with the monomericsteroid derivative 6a,9a-difluoro-16a-methyl-prednisolone- 21diethyleneglycol monomethyl-ether carbonate (II) which had been preparedas follows:

A solution of 90 mg. of diethyleneglycolmonomethylethermonochloroformiate in 1 ml. of absolute dioxane was added dropwise,while stirring, at 0 C. to a solution of 200 mg. of6a,9a-difluoro-16a-methyl-prednisolone in 1.5 ml. of absolute dioxaneand 1.5 ml. of absolute pyridine. After stirring had been continued for16 hours at 20 C., the reaction mixture was poured onto water/sodiumcarbonate solution, whereupon crystals precipitated. After filtering,washing with water, drying and digesting with a small amount of ether,152 mg. of 6a,9a-difiuoro-16amethyl prednisolone21-diethylene-glycol-monomethylether carbonate having a melting point of144-146 C. were obtained.

The local inflammation-inhibiting properties of the reaction productswere pharmacologically tested following the granuloma pouch test.

25 ml. of air were injected in the middle of the back skin of femaleSpague-Dawley rats having an initial body weight of from 150 to 200 g.and 0.5 ml. of a 1% croton oil was introduced into this air pouch. After48 hours the air was removed under vacuum and after 72 hours theadhesion that had taken place was loosened.

\For testing their local activity the substances were dissolved in 0.2ml. of sesame oil and were directly injected once a day into the airpouch. On the eighth day after formation of this air pouch the animalswere killed and the volume of the exudate that had collected in thepouch was measured. The amount of exudate taken from the tested groupwas gathered and compared with the amount obtained from the untreatedcontrol group. The inhibition of exudation is indicated in percentage.

Graphical evaluation of the probability system shows that substance I isfour times as effective as substance II. That is, dimerizing thecorticoid-Zl-carbonates with a 2l-alkyl-carbonate radical, for examplein the above case, an activity is achieved in the granuloma pouch testwhich is at least four times higher than that of the correspondingmonomeric comparison substance II.

Because of their good anti-inflammatory effect, the products of theinvention may advantageously be used in veterinary and human therapy fortreating inflammatory dermatoses of the most different geneses in theform of suspensions, ointments, creams or sprays, as well as, forexample, for local treatment in the form of crystal suspensions, forexample for intra-articular injections.

The following examples serve to illustrate the invention, but they arenot intented to limit it thereto. Melting points were determined on aKofier heating bench and are uncorrected.

EXAMPLE 1 A solution of 245 mg. oftrans-cyclohexylene-[1,4-bischloroformiate] (=bis-chlorocarbonate oftrans-quinital) in 2 ml. of absolute dioxane was added dropwise, whilestirring, at 0 C. to a solution of 660 mg. of ll-desoxycorticosterone in4 ml. of absolute pyridine, whereupon a white precipitate separated.After stirring had been continued for 4 hours at 0 C., the reactionmixture was left to stand for 16 hours at 20 C. Then it was poured ontoan aqueous solution of sodium bicarbonate and washed with littlemethanol, whereupon white crystals precipitated at once. These werefiltered, washed carefully with water and dried over P 0 in vacuo. Afterdigesting the crystals in ether, 668 mg. of trans-quinitalbis-[lldesoxy-corticosterone 21]-carbonate having a melting point of 210-215 C.were obtained which after recrystallization from methylenechloride/ether showed a melting point of 228 C.

Typical infrared bands: at 1,740; 1,715; 1,660; 1,605; 1,250 cmr no moreOH-bands were present.

EXAMPLE 2 EXAMPLE 3 A solution of 126 mg. oftriethyleneglycol-bis-chloroformiate in 2.5 ml. of absolute dioxane wasadded dropwise while stirring at C. to a solution of 360 mg. of6m-methyl-9a-fluoro-prednisolone in 2 ml. of absolute pyridine,whereupon a precipitate separated. After stirring had been continued for3 /2 hours at 0 C. the reaction mixture was left to stand for 18 hoursat 23 C. Subsequently the mixture was poured on about 50 ml. of watercontaining sodium carbonate and then washed with a small amount ofmethanol. After some time a white crystallized precipitate separated.The precipitate was filtered, carefully washed with water, dried invacuo over phosphorus pentoxide and digested with cold ether. 293 mg. oftriethyleneglycol bis[6u methyl-9or-fluoro-prednisolone-211-carbonatehaving a melting point of 153- 154 C. were obtained. Afterrecrystallization from a small amount ofmethylenechloride/ether-cyclohexane the product of the invention showedthe melting point of 155156 C.

Typical infrared bands: 3,430; 1,745; 1,720; 1,655; 1,605; 1,260; 1,120cmr EXAMPLE 4 In the same manner as disclosed in Example 3, a solutionof 360 mg. 6a-methyl-9a-fluoro-prednisolone in 2 ml. of pyridine wasreacted with a solution of 146 mg. oftetraethyleneglycol-bis-chloroformiate in 2.5 ml. of dioxane and thereaction product obtained was worked up. 326 mg. oftetraethyleneglycol-bis-[6u-methyl-9afiuoro-prednisolone-Z1]-carbonatehaving a melting point of 235-240- C. were obtained (after previoussintering).

Typical infrared bands: 3,4203,460; 1,745; 1,720; 1,650; 1,605; 1,260;1,115 cmr EXAMPLE 5 In the same manner as disclosed in Example 3, asolution of 300 mg. of 6a,9u-difluoro-16a-methyl-prednisolone in 2 ml.of absolute pyridine and 2 ml. of absolute dioxane was reacted with asolution of 117 mg. of tetraethyleneglycol-bis-chloroformiate in 1.5 ml.of absolute dioxane and the reaction product obtained was worked up. 285mg. oftetraethyleneglycol-bis[6a,9a-difiuoro-16a-methyl-prednisolone-2l]-carbonatehaving a melting point of 268-270 C. were obtained.

Typical infrared bands: 3,400; 3,420; shoulder at 3,550; 1,750; 1,720;1,660; 1,620; 1,260; 1,130 l,140 cm.-

EXAMPLE 6 Diethyleneglycol-bis- [6d,90t-dlfil10l0-160t-methy1-prednisolone-Z l -carbonate In the same manner as disclosed in Example3, a solu tion of 288 mg. of 6a,9a-difiuoro-16a-rnethyl-prednis0lone in2 ml. of absolute pyridine was reacted with a solution of 90 mg. ofdiethyleneglycol-bis-chloroformiate in 2 ml. of absolute dioxane and thereaction product was worked up. After the reaction mixture had beenpoured onto a mixture of water and sodium carbonate solution, thereaction product, which at first had precipitated in an oily form,slowly crystallized after having been left for several days (andtriturated at the wall of the glassvessel). The crystals were filteredoff, carefully washed with water, dried and digested with a small amountof cold ether. 272 mg. of diethyleneglycol =bis[6a,90L-difi110r0-16mmethyl-prednisolone-Zl]-carbonate having a meltingpoint of 157160 C. were obtained (after previous sintering). Theinfrared spectrum showed a location of the bands which was similar tothe reaction products obtained in Examples 2-5.

EXAMPLE 7 A solution of 750 mg. of triethylene-glycol-bis-chloroformiatein 2 ml. of absolute dioxane was added dropwise while stirring at 0 C.to a solution of 1.8 g. of prednisolone in 10 ml. of absolute pyridine.After having been left for 16 hours at 20 C. the mixture was poured ontoa mixture of water and sodium chloride solution,

whereupon an oil precipitated. The aqueous phase was decanted, the oilwas taken up with ether and the ether 5 was evaporated to a largeextent. The reaction product was obtained in crystalline form. Afterfiltration, 1.34 g. of triethyleneglycol-bis- [prednisolone-21-carbonate having a melting point of 139-140 C. were obtained.

Typical infrared bands: 3,440; 1,750; 1,725; 1,655; 1,610; 1,260; 1,110cm.

EXAMPLE 8 In the same manner as disclosed in Example 7, 3.6 g. ofprednisolone, dissolved in 20 ml. of pyridine, were reacted with asolution of 1.3 g. diethyleneglycol-bis-chloroformiate in 3 ml. absolutedioxane and the reaction product obtained was worked up. 2.74 g. ofdiethyleneglycolbis-[prednisolone-21]-carbonate having a melting pointof 160-165 C. were obtained (the melting point was not typical since itcomprised too broad a range).

Typical infrared bands: 3,450; 1,745; 1,720; 1,650: 1,610; 1,260; 1,105cmr EXAMPLE 9 Trans-quinital-bis- [6a-methyl-prednisolone-21] -carbonate In the same manner as disclosed in Example 1, a solution of 3.74g. of 6u-methyl-prednisolone in 25 ml. of absolute pyridine was reactedwith a solution of 1.3 g. of cyclohexylene-[1,4-bis-chloroformiate] in11 ml. of absolute dioxane and the reaction product was worked up. 4.3

g. of crude trans-quinital-bis-[6a-methyl-prednisolone-21]- carbonatewere obtained which after recrystallization from tetrahydrofurane/etherhad a melting point of 263 C. Typical infrared bands: 3,460-3,480; 1,745(shoulder);

EXAMPLE l0 Ethyleneglycol-bis- [6a-methyl-prednis olone-21 carbonate Inthe same manner as disclosed in Example 1, a solution of 374 mg. of6a-methyl-prednisolone in 3 ml. of absolute pyridine was reacted with asolution of 103 mg. ethyleneglycol-bis-chloroformiate in 1 ml. ofabsolute dioxane and the reaction product was worked up. The reactionproduct, which precipitated first in an oily form, slowly crystallizedafter having been digested several times with distilled water. Afterisolation, 323 mg. of dried ethyleneglycol-bis-[6oc methylprednisolone-21]-carbonate were obtained which after digesting withether had a melting point of l91-196 C.

Typical infrared bands: 3,430; 1,750; 1,720; 1,650; 1,605; 1,285; 1,230cmr' EXAMPLE 11 Neopentylglycol-bis- [6a-methyl-prednisolone-21 1-carbonate n-Hexanel ,6-diol-bis- [6a-methyl-prednisolone-2l 1- carbonateIn the same manner as disclosed in Examples 1 and 10, a solution of 374mg. of om-methyl-prednisolone in 3 ml. of pyridine was reacted with 128mg. of n-hexane- 1,6-diol-bis-chloroformiate dissolved in 1 ml. ofdioxane and the reaction product obtained was worked up. After digestingthe product with ether, 243 mg. of n-hexane-1,6-diol-bis-[6a-methyl-prednisolone-21J-carbonate having a meltingpoint of 166170 C. were obtained.

Typical infrared bands: 3,440; 1,740 (shoulder); 1,715; 1,645; 1,600;1,255 CID-1.

EXAMPLE 13 Ethylene glycol-bis- 9oc-fll10l'0- 1 6a-methyl-prednisolone-21]-carbonate In the same manner as disclosed in Example 1, a solutionof 196 mg. of dexamethasone in 3 ml. of pyridine was reacted with asolution of 55 mg. of ethyleneglycolbis-chloroformiate in 1 ml. ofdioxane and the reaction product *was worked up. The reaction product,which precipitated in oily form, was isolated in the usual manner byextracting with chloroform, washing etc. and the oil obtained wascrystallized by digesting with ether. After filtration, crystallizedethyleneglycol-bis-[6a-fiuoro-16amethyl-prednisolone-2l]-carbonatehaving a melting point of 226 C. was obtained.

Typical infrared bands: 3,450; 1,750; 1,720; 1,655; 1,610; 1,285; 1,230cm.-

EXAMPLE 14Ethyleneglycol-bis-[6a,9a-difluoro-16a-methylprednisolone-Zl]-carbonateEXAMPLE 15 Trans-quinital-bis-[9a-fiuoro-16u-methyl-prednisolonc-21]-carbonate In the same manner as disclosed in Example 2, 196 mg. ofdexamethasone were reacted and the reaction product was worked up. Afterdigesting the product with ether, 162 mg. oftrans-quinital-bis-[9a-fiuoro-16a-methyl-prednisolone-21]-carbonatehaving a melting point of 198- 200 C. were obtained. Afterrecrystallization from methylene chloride/tetrahydrofurane/ether, themelting point was 216217 C.

Typical infrared bands: 3,420; 1,740 (shoulder); 1,715; 1,650;1,600-1,610; 1,260 cmr EXAMPLE 16 T rans-quinitol-bis-Ga-flLIOI'O-PredniSOlOfle-Z l -carbonate In the same manner as disclosedin Example 1, a solution of 380 mg. of 6u-fluoro-prednisolone in 2.5 ml.of pyridine was reacted with a solution of 130 mg. ofcyclohexylene-[1,4-bis-chloroformiate] in 1.5 ml. of dioxane and thereaction product obtained was worked up. 282 mg. oftrans-quinitol-bis-[6a-flu0ro-prednis0lone-21]-carbonate having amelting point of 190 C. were obtained.

Typical infrared bands: 3,460; 1,745; 1,720; 1,655; 1,620; 1,260 C111.1.

EXAMPLE 17 Neopcntylglycol-bis- [6a-fiuoro-prednisolOne-Z l carbonate Inthe same manner as disclosed in Examples 1 and 10, a solution of 380 mg.of 6a-fiuoro-prednisolone in 3 ml. of pyridine was reacted with asolution of 122 mg. of neopentylglycol-bis-chloroformiate and thereaction product was worked up. After digesting with ether, 244 mg. ofneo- 8 pentylglycol bis [6a-fiuoro-prednisolone-2l]-carbonate having amelting point of 186190 C. were obtained.

Typical infrared bands: 3,460; 1,750; 1,720; 1,660; 1,620; 1,260 cm.

EXAMPLE l81.4-dimethyl-quinitol-bis-[6a,9a-di'fluoro-16a-methylprednisolone]-carbonate In the same manner as disclosed in Example 2 or 1, 205 mg. of6a,9a-difiuoro-16ot-methyl-prednisolone were reacted with mg. of1,4-dimethylcyclohexylene-[1.4-bischloroformiate] and the reactionproduct obtained was worked up. 173 mg. of crude1,4-dimethyl-quinitol-bis- [6a,9adifluoro-l6a-methyl-prednisolone-2l]-carbonate having a melting point of190198 C. were obtained. This was recrystallized from methylenechloride/ ether.

Typical infrared bands: 3,450-3,480; 1,7351,750 (shoulder); 1,720;1,655; 1,615; 1,2501,260 cmf EXAMPLE 191,4-dimethyl-quinital-bis-[6a-methyl-prednisolone-21]- carbonate In thesame manner as disclosed in Example 18, mg. of 6a-methyl-prednisolonewere reacted. After an analogous work-up, 148 mg. of crystallized1,4-dimethylquinite bis-[6a-methyl-prednisolone-2l]-carbonate wereobtained having the typical infrared bands: 3,4603,480; 1,740-1,745(shoulder); 1,720; 1,655; 1,610; 1,255 CHI-"1.

EXAMPLE 20 Neopentylglycol-bis-6a,9a-difiuoro-16a-methylprednisolone-21]-carbonate In the same manneras disclosed in Example 13, 205 mg. of6a,9u-difluoro-l6a-methyl-prednisolone were reacted with 70 mg. ofneopentylglycol-bis-chloroformiate and the reaction product was workedup. After digesting with ether, 164 mg. ofneopentylglycol-bis-[6a,9a-difiuoro-16a-methyl-prednisolone-2lJ-carbonate having a melting point of 228234C. were obtained. After recrystallization from methylene chloride/ether,this showed the following typical infrared bands: 3,4403,480; 1,745(shoulder); 1,720; 1,655; 1,605-1,615; 1,255 cmf EXAMPLE 21Neopentylglycol-bis- [9a4fluoro-16a-methyl-prednisolone- 21 J-carbonateIn the same manner as disclosed in Example 20 or 13, 196 mg. ofdexamethasone were reacted with 70 mg. ofneopentylglycol-bis-chloroformiate and the reaction product was workedup. 174 mg. ofneopentylglycol-bis-[9afiuoro-l6a-methyl-prednisolone-21]-carbonatehaving a melting point of 186191 C. were obtained.

Typical infrared bands: 3,440; 1,745 (broad shoulder);1,720;1,655;1,605-1,615;1,260 cmr We claim:

1. A bis-[steroid-21]-alkyl-carbonatc of the formula wherein X ishydrogen,

Y is hydrogen or fluorine; Z is hydrogen, fluorine, or methyl; R is--(CH OHzOH wherein X, Y, Z, R and R are defined as in claim 1, in aninert solvent in the presence of an acid scavenger and at a temperaturefrom -40 C. to the boiling point of the solvent employed, with oneequivalent of a bis-chloroformiate of the formula O 01-iioR10o -c1wherein R is as defined in claim 1.

3. Trans cyclohexylene l,4-bis[l l-desoxycorticosterone-21 -arbonate.

4. Trans cyclohexylene1,4-biS-[6a,9oc-diflu0I'O-1-6amethyl-prednisolone-Z 1 -carbonate.

5. Diethyleneglycol bis [6u,9a-difiu0ro-16a-methylprednisolone-21]-carbonate.

6. Diethyleneglycol-bis- [prednisolone-21] carbonate.

7. T rans-cyclohexylene-1,4-bis-[6ot-methylprednisolone- ZIJ-carbonate.

8. Transcyclohexylene-1,4-bis[9ot-fluoro-16a-methylprednisolone-21]-carbonate.

9. Trans cyclohexene-lA-bis[6a-fluoro-prednisolone- 21 -carb0nate.

10. A pharmaceutical composition containing an effective amount of abis-[steroid-21]-alkyl-carbonate as defined in claim 1 as the activeingredient thereof.

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R. 424243

